1. Field of the Invention
This invention relates to compounds useful for the synthesis of (+)-discodermolide and methods for their preparation.
2. Description of Related Art
(+)-Discodermolide (hereinafter “discodermolide”) is a polyketide natural product isolated from the marine sponge Discodermia dissoluta (Gunasekera et al., U.S. Pat. No. 4,939,168 (1990) and U.S. Pat. No. 5,840,750 (1998)). It is a potent inhibitor of tumor cell growth, acting via a microtubule stabilization mechanism, and is presently undergoing phase I clinical trials as an anti-cancer agent.

The supply of discodermolide from natural sources is meager, because the sponge usually inhabits depths where it is harvestable only by submersible vehicles and produces discodermolide in very low concentrations. It is believed that the actual producing organism is a microbial symbiont inside the sponge and not the sponge itself, but efforts to isolate and culture the symbiont have been unsuccessful to date, precluding such an approach to an increased discodermolide supply. Consequently, the availability of discodermolide for clinical trials and research is dependent on material made by chemical synthesis. To date, at least six different total syntheses of discodermolide have been reported, by:                (1) The Smith group at the University of Pennsylvania (the “Smith synthesis”): Smith et al., J. Am. Chem. Soc., 117, 12011 (1995); Smith et al., Org. Lett., 1, 1823 (1999) (additions and corrections Org. Lett. 2, 1983 (2000); Smith et al., J. Am. Chem. Soc., 112, 8654 (2000).        (2) Novartis Pharma AG (the “Novartis synthesis”): Mickel et al., Org. Proc. Res. Dev. 8 (1), 92 (2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 101(2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 107 (2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 113 (2004); Mickel et al., Org. Proc. Res. Dev. 8 (1), 122 (2004).        (3) The Paterson group at Cambridge University (the “Paterson synthesis”): Paterson et al., Angew. Chem. Int. Ed., 39, 377 (2000); Paterson et al., Tetrahedron Lett., 41, 6935 (2000); Paterson et al., J. Am. Chem. Soc., 123, 9535-9544 (2001); Paterson et al., Org. Lett., 5, 35 (2003).        (4) The Myles group at UCLA: Harried et al., J. Org. Chem., 62, 6098 (1997); Harried et al., J. Org. Chem., 68 (17), 6646-6660 (2003).        (5) The Schreiber group at Harvard University: Nerenberg et al., J. Am. Chem. Soc. 115, 12621 (1993); Hung et al., J. Am. Chem. Soc., 118, 11054 (1996).        (6) The Marshall group at the University of Virginia: Marshall et al., J. Org. Chem., 63, 7885 (1998).        
A review of the various syntheses has been published: Paterson et al., Eur. J Org. Chem., 12, 2193 (2003). Additionally, many partial syntheses have been reported for one discodermolide synthon or another.
The Smith and Novartis syntheses stand out because they are scalable to gram or multi-gram quantities. FIG. 1 shows the architecture of the Novartis synthesis, which borrows concepts from the Smith and Paterson syntheses. It relies on a common intermediate B (derived from the commercially available Roche ester A) as the source of discodermolide's thrice-repeated stereochemical triad of three consecutive asymmetric carbon atoms (identified by dots (•) in FIG. 1). Common intermediate B in turn leads to intermediates C, D, and E, from which backbone carbons C9-C14, C15-C21, and C1-C6 are respectively derived. The synthesis of intermediate E is particularly onerous, requiring 11 linear steps. Mickel et al., Org. Proc. Res. Dev. 8 (1), 92 (2004). Coupling of intermediates C, D, and E, plus ancillary reactions, leads ultimately to discodermolide itself.
Thus, it is desirable to increase the availability of discodermolide by designing a more efficient synthesis de novo or by improving the efficiency of one of the extant ones, by providing for more efficient synthesis of intermediates useful in existing synthetic approaches. A disclosure in the latter vein is Santi et al., US 2004/0018598 A1 (2004), the disclosure of which is incorporated herein by reference.